Medication overuse headache (MOH) is a chronic daily headache that develops from the frequent use of medications taken for the treatment of migraine headache pain. Despite its clinical significance, the underlying mechanisms of MOH remain unknown. We hypothesize that chronic use of analgesics leads to neuro-adaptive changes in the nervous system that causes an increase in the excitability of neurons involved in headache pain. Although several studies have provided indirect evidence for chronic morphine-induced sensitization of nociceptive signals, direct electrophysiological evidence is lacking. Using extracellular single unit recordings, the proposed experiments will examine the effects of sustained morphine administration in rats on the properties of spinal trigeminal nucleus (Vsp) neurons relevant to headache pain. We will test the hypothesis that sustained morphine administration up-regulates pronociceptive systems, as indicated by an increase in the excitability of dura sensitive Vsp neurons (Aim 1). Additional experiments will test the hypothesis that descending facilitation from the rostral ventromedial medulla (RVM) is necessary for the increased excitability of Vsp dura sensitive neurons following sustained morphine exposure (Aim 2). As part of these aims we will also test the hypothesis that chronic morphine induced increases in descending facilitation from the RVM interferes with counter-irritation, as defined by the inhibition of dura sensitive neurons produced by the application of a remote noxious stimulus. Significantly, patients with chronic daily headache have been shown to lack the normal inhibition of pain produced by counter-irritation. The overall goal of this research is to study how chronic drug exposure can produce neuro-adaptive changes in dura sensitive neurons that may lead to an increased frequency of headaches. Medication overuse headache represents a major clinical problem, affecting 1-2 percent of the general population, and can be caused by overuse of opiates, triptans and "over-the-counter" analgesics. The proposed experiments will provide insight into how sustained morphine exposure can modulate headache-related neural pathways. Understanding the neuro-adaptive changes that occur with chronic morphine exposure will lead the way to new therapeutic strategies to treat headache patients while reducing the risk of developing MOH. [unreadable] [unreadable] [unreadable]